An antibody heavy chain constant region sequence enhancing activity of an agonistic antibody

A heavy chain constant region and constant region technology, which is applied in the direction of antibodies, anti-receptor/cell surface antigen/cell surface determinant immunoglobulin, antibody medical components, etc., can solve the problems that antibody research and development has not been successful, and achieve good development Prospect, good safety profile, enhanced activity effect

Active Publication Date: 2017-12-15
SHANGHAI JIAOTONG UNIV SCHOOL OF MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, although agonistic tumor immunotherapy antibodies have proved their great potential in animal models and have become a widely accepted and optimistic concept of tumor immunotherapy, the development of such antibodies has not been successful so far, and it is an important field in the field of tumor immunotherapy. a major current challenge

Method used

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  • An antibody heavy chain constant region sequence enhancing activity of an agonistic antibody
  • An antibody heavy chain constant region sequence enhancing activity of an agonistic antibody
  • An antibody heavy chain constant region sequence enhancing activity of an agonistic antibody

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0137] Example 1. The heavy chain constant region of the present invention and the agonistic antibody comprising the sequence of the heavy chain constant region of the present invention

[0138] Through the above-mentioned gene cloning and expression purification techniques, the present invention has constructed a series of specific examples of different heavy chain constant regions, and constructed anti-human CD40 or anti-mouse CD40 antibodies based on these heavy chain constant regions and antibodies against mouse DR5.

[0139] In general, in a specific embodiment of the present invention, the heavy chain constant region is divided into two parts for research and optimization, including the CH1-hinge region part and the CH2-CH3 domain part. The CH1-hinge region part means a segment consisting of an antibody CH1 domain and a hinge region, and the CH2-CH3 domain part means a segment consisting of an antibody CH2 domain and a CH3 domain. In a specific embodiment, the CH1-hinge...

Embodiment 2

[0156] Example 2. The activity of human IgG agonistic antibodies is dependent on the interaction of antibody Fc with Fcγ receptors

[0157] In order to investigate whether the activity of human IgG agonistic antibodies is regulated by the interaction between antibody Fc and Fcγ receptors, agonistic anti-mouse CD40 antibodies (Anti-mCD40-hIgG1, Anti-mCD40-hIgG2, Anti-mCD40-hIgG3, Anti-mCD40-hIgG4) were first used as model antibodies to study whether their immune activation activity was affected by the expression of Fcγ receptors.

[0158] Since agonistic CD40 has immune activation activity that promotes the activation of antigen-presenting cells and induces the activation and expansion of antigen-specific CD8-positive T cells, agonistic human anti-mouse CD40 antibody (Anti-mCD40-hIgG) promotes OVA pattern antigen-specific CD8 The ability to activate and expand positive T cells in OVA-immunized mice was used to evaluate their immune activation activity (Science. 2011A μg 19; 333...

Embodiment 3

[0161] Example 3. Specific interaction of human inhibitory Fcγ receptor (hFcγRIIB) with antibody Fc promotes activity of agonistic human anti-CD40 antibody.

[0162] To analyze the specific Fcγ receptors in the Fcγ receptor family that specifically provide human IgG agonistic antibody activity-dependent Fc-Fcγ receptor interactions, the contribution of the human inhibitory Fcγ receptor hFcγRIIB was further analyzed. Inhibitory Fcγ receptor humanized mice (Fcgr2b - / - hFCGR2B Tg ) and control mice (Fcgr2b - / - ), Anti-mCD40-hIgG2 antibody in Fcgr2b - / - No activity in mice ( Figure 4 C), while in inhibitory Fcγ receptor humanized mice (Fcgr2b - / - hFCGR2B Tg ) in the activity (approximately nearly 80% OT-I CD8 + , Figure 4 C) and in humanized mice expressing all human Fcγ receptors (hFCGR Tg ) Medium activity (approximately nearly 60-80% OT-I CD8 + , Figure 4 A) Comparable, indicating that human inhibitory Fcγ receptors are sufficient to provide support for Anti-mCD40-...

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Abstract

The invention provides a heavy chain constant region. The heavy chain constant region includes a CH1 structural domain, a hinge region, a CH2 structural domain and a CH3 structural domain. Sequences of the CH1 structural domain and the hinge region are sequences derived from a CH1 structural domain and a hinge region of human IgG2. Sequences of the CH2 structural domain and the CH3 structural domain are sequences derived from a CH2 structural domain and a CH3 structural domain of human IgG. Affinity between the antibody heavy chain constant region to human Fc[gamma]IIB is equal to or higher than affinity between human IgG1 and the human Fc[gamma]IIB. The I / A ratio of the antibody heavy chain constant region is equal to or higher than the I / A ratio of the human IgG1. An antibody or fusion protein based on the heavy chain constant region is also provided. The antibody heavy chain constant region can significantly enhance agonist activity of the antibody or the fusion protein, and can improve treatment effects of the antibody or the fusion protein on tumor, autoimmunity, and other diseases.

Description

technical field [0001] The present invention relates to the field of biopharmaceuticals, in particular to a heavy chain constant region sequence and molecule capable of enhancing the activity of an agonistic antibody or an agonistic molecule (a fusion protein comprising a heavy chain constant region sequence), and a method based on the heavy chain constant region Constructed antibodies or fusion proteins. Background technique [0002] Molecular targeted therapy based on antibodies and heavy chain constant regions (including Fc fragments), including antibody and heavy chain constant region fusion proteins, has achieved great success in the field of biopharmaceuticals for nearly three decades and continues to be the focus of this field. The treatment of various diseases provides new methods and possibilities. About 30 biotherapeutics (including molecules of heavy chain constant region fusion proteins) based on the heavy chain constant region have been approved, and more than ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/28A61K39/395A61K39/39A61P35/00A61P37/04A61P29/00
CPCC07K16/2878C07K2317/24C07K16/00C07K16/28G01N33/6854C07K2317/52C07K2317/73C07K2317/76C07K2317/92A61K39/00A61K39/39A61K39/395C07K16/46G01N33/68A61P37/04A61P35/00A61K2039/505C07K16/30A61K2039/585C07K2317/522C07K2317/524C07K2317/526C07K2317/528C07K2317/53C07K2317/21C07K2317/72C07K2317/75C07K2317/569
Inventor 李福彬刘小波张燕赵英杰石欢张慧慧
Owner SHANGHAI JIAOTONG UNIV SCHOOL OF MEDICINE
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